key: cord-0943547-rc2ag2pg
authors: Chen, Rui; Ren, Cuiping; Liu, Miao; Ge, Xiaopeng; Qu, Mingsheng; Zhou, Xiaobo; Liang, Mifang; Liu, Yan; Li, Fuyou
title: Early Detection of SARS-CoV-2 Seroconversion in Humans with Aggregation-Induced Near-Infrared Emission Nanoparticle-Labeled Lateral Flow Immunoassay
date: 2021-04-30
journal: ACS Nano
DOI: 10.1021/acsnano.1c01932
sha: 83ef9ddc8051c09a6c28b68674548d0b1df5aed6
doc_id: 943547
cord_uid: rc2ag2pg

[Image: see text] An outbreak of coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses great threats to human health and the international economy. To reduce large-scale infection and transmission risk of SARS-CoV-2, a simple, rapid, and sensitive serological diagnostic method is urgently needed. Herein, an aggregation-induced emission (AIE) nanoparticle (AIE(810)NP, λ(em) = 810 nm)-labeled lateral flow immunoassay was designed for early detection of immunoglobulin M (IgM) and immunoglobulin G (IgG) against SARS-CoV-2 in clinical serum samples. Using a near-infrared (NIR) AIE nanoparticle as the fluorescent reporter (△λ = 145 nm), the autofluorescence from the nitrocellulose membrane and biosample and the excitation background noise were effectively eliminated. After optimization, the limit of detection of IgM and IgG is 0.236 and 0.125 μg mL(–1), respectively, commensurate with that of the enzyme-linked immunosorbent assay (ELISA) (0.040 and 0.039 μg mL(–1)). The sensitivity of the proposed AIE(810)NP-based test strip for detecting IgM and IgG is 78 and 95% (172 serum samples), commensurate with that of ELISA (85 and 95%) and better than that of a commercial colloidal gold nanoparticle (AuNP)-based test strip (41 and 85%). Importantly, the time of detecting IgM or IgG with an AIE(810)NP-based test strip in sequential clinical samples is 1–7 days after symptom onset, which is significantly earlier than that with a AuNP-based test strip (8–15 days). Therefore, the NIR-emissive AIE nanoparticle-labeled lateral flow immunoassay holds great potential for early detection of IgM and IgG in a seroconversion window period.

Because of the advantages of portability, rapidity, simplicity, and low cost, the traditional colloidal gold nanoparticle (AuNP)-based lateral flow immunoassay is widely used in point-of-care testing (POCT) of COVID-19. 17 For example, Brochot et al. developed a AuNP-based test strip that has a positive rate of 60−80% on day 10 and 100% on day 15 for the detection of IgG. 21 To improve the sensitivity of the rapid test strip, Wang et al. developed a surface-enhanced Raman scattering (SERS)-based lateral flow test strip, and the detection limit of IgM and IgG is 800 times lower than that of the AuNP-based test strip. 22 To further satisfy the need for the detection of IgM and IgG under challenging circumstances, such as community and port entry/exit, and to efficiently prevent the SARS-CoV-2 transmission, the lateral flow immunoassay must be sensitive and easy to operate. Fluorescence lateral flow detection platform has been recognized as an important POCT detection technology due to its advantages of high sensitivity and portable instrumentation. Therefore, a simple, rapid, and sensitive fluorescence lateral flow test strip is urgently needed to early detect IgM and IgG against SARS-CoV-2 in human serum.

In this study, we demonstrated a near-infrared (NIR) emissive lateral flow immunoassay with an aggregation-induced emission (AIE) dye-loaded nanoparticle as reported that could detect IgM and IgG against SARS-CoV-2 in 1−7 days after symptom onset. To avoid the interference of autofluorescence in a nitrocellulose (NC) membrane and biosample, 23−25 an AIE dye with NIR emission, namely, BPBT, was chosen as the fluorescent unit. To further amplify the fluorescent labeling signal of a detection ligand, a polystyrene (PS) nanoparticle with a size of 300 nm loaded with 3.18 × 10 6 dyes (AIE 810 NP) was developed to label the detection ligand (Scheme 1a). Additionally, a portable reader was developed to quantitatively read out the NIR fluorescence signal (Scheme 1c). Using AIE 810 NP-labeled SARS-CoV-2 antigen (AIE 810 NP-SARS-CoV-2 antigen) as the fluorescent probe (Scheme 1b), the test strip achieved a diagnostic sensitivity of 78 and 95% for IgM and IgG, respectively, superior to that of the commercial AuNP-based test strip (41 and 85%). More importantly, the AIE 810 NP-based test strip can detect IgM or IgG at 1−7 days after symptoms onset, earlier than that of the AuNP-based test strip (8−15 days) . Overall, the developed AIE 810 NP-based test strip holds great promise for early detection of IgM and IgG against SARS-CoV-2 in clinical serum samples.

Principle of the NIR-Emissive AIE Nanoparticle-Labeled Lateral Flow Immunoassay. On basis of the immunoreaction between IgM/IgG and the AIE 810 NP-SARS-CoV-2 antigen, the combined IgM−IgG lateral flow test strip is designed for the detection of IgM and IgG in a clinical serum sample (Scheme 1b). A portable reader was built to collect the NIR fluorescence signal from three lines, which comprises an LED lamp excited at 680 nm, a CMOS camera, and a set of optical elements (Scheme 1c). For human serum sample detection, the IgM and IgG are captured by an AIE 810 NP-SARS-CoV-2 antigen and then captured by the mouse antihuman IgM immobilized on the M line and mouse anti-human IgG immobilized on the G line (forming a sandwich immunocomplex), respectively. The AIE 810 NP-labeled chicken IgY (AIE 810 NP-chicken IgY) is specifically bound to goat antichicken IgY immobilized on the C line as a quality control signal. The test results for the detection of IgM and IgG using the AIE 810 NP-based test strip are displayed in Scheme 1d. In the presence of IgM and IgG, fluorescent bands appear on all of the M lines, G lines, and C lines under 680 nm excitation of an LED lamp (IgM/IgG positive); in the presence of IgM, fluorescent bands appear on both of the M line and C line (IgM positive); in the presence of IgG, fluorescent bands appear on both of the G line and C line (IgG positive). However, in the absence of IgM and IgG, no fluorescent bands on the M and G lines (IgM/IgG negative) could be observed. Notably, if the fluorescent band of the C line is not observed, the strip is invalid.

Synthesis and Characterization of the NIR-Emissive AIE Nanoparticle. In this test strip, a NIR-emissive AIE molecule (BPBT) was selected as a fluorescent unit (Figures S1−S4, Supporting Information). 26, 27 The AIE properties of BPBT were checked by monitoring its fluorescence intensity (FL intensity) in THF/water mixtures with variable water volume fractions (f w ). A significant increase in the fluorescence intensities of BPBT is observed upon the gradual enhancement of f w from 50 to 90% (water/THF, v/v), and gradual blue shifts are observed for the emission maxima (from 890 to 837 nm), owing to their twisted intramolecular charge transfer (TICT) state ( Figure S5 , Supporting Information). 28 The absorption spectra of BPBT with diverse f w were also investigated during the AIE titration experiment. The absorption maxima decrease gradually and shift from 633 to 665 nm ( Figure S6 , Supporting Information), owing to the formation of a different aggregated state. 29 For in vitro diagnosis, BPBT molecules were encapsulated into PS nanoparticles using an organic solvent swelling method (Scheme 1a). 30 Transmission electron microscopy (TEM) images in Figure 1a ,b show the morphologies of PS nanoparticles and AIE 810 NP, respectively. The physical photos of the PS nanoparticles and AIE 810 NP are shown in Figure 1a ,b inset, which indicates that the BPBT are successfully embedded in PS nanoparticles. The hydrodynamic diameter of AIE 810 NP was similar to that of PS nanoparticles ( Figure S7 , Supporting Information), demonstrating no aggregation or rupture of the PS nanoparticle carrier after dye loading. The UV−vis absorption spectrum and fluorescence spectrum of the synthesized AIE 810 NPs were further characterized. Figure 1c shows that the absorption maximum of the AIE 810 NP is 665 nm. Moreover, by establishing the UV absorption standard curve of BPBT, the number of BPBT in an AIE 810 NP was calculated to be 3.18 × 10 6 ( Figure S8 , Supporting Information). Figure 1d shows that the emission maximum of the synthesized AIE 810 NP is 810 nm. At the same time, there was no fluorescence in PS nanoparticles with the same concentration ( Figure S9 , Supporting Information), which indicated that BPBT was successfully embedded in the PS nanoparticle. In addition, the emission maximum of AIE 810 NPs is blue-shifted relative to BPBT (from 890 to 810 nm), due to their TICT state. 28 The quantum yield (QY), photostability, thermal stability, and colloidal stability of AIE 810 NPs were characterized. The QY of AIE 810 NP was determined using indocyanine green (ICG, QY = 1.6%) in water as a reference. 28 The QY of AIE 810 NP was calculated to be 2.1% ( Figure S10 , Supporting Information). The photostabilities of AIE 810 NP and BPBT were evaluated by monitoring the FL intensity under continuous radiation with a 730 nm laser (1 W cm −2 ). Given its wide utility in fluorescent bioanalysis, cyanine dye derivative (abbreviated as Cy7) was chosen as a reference for comparison (Figures S11 and S12, Supporting Information). 31−33 AIE 810 NP and BPBT show 6.5 and 3.3% loss of FL intensity after 60 min of continuous radiation, respectively, whereas Cy7 shows a 98% loss of FL intensity after 30 min of ACS Nano www.acsnano.org Article continuous radiation (Figure 2a ), demonstrating that BPBT and AIE 810 NP have excellent photostability. The thermal stability of AIE 810 NP was evaluated by incubating it in water at 50°C for 1 week. The loss in FL intensity of AIE 810 NP is 12.6%, whereas that of Cy7 is 67.5% (Figure 2b ), revealing a better thermal stability for AIE 810 NP. In addition, the hydrodynamic diameter of AIE 810 NPs stored at 37°C for 1 week is the same as before (Figure 2c ), presumably due to the existence of a large number of negative-charged carboxyl groups on the surface of AIE 810 NP ( Figure S13 , Supporting Information), indicating that the AIE 810 NP has excellent colloidal stability. All of these results indicate that the synthesized AIE 810 NP is suitable to be used as a fluorescent reporter for test strip detection.

Optimization of Immunoreaction Conditions. To ensure the specific binding of AIE 810 NP to IgM/IgG, SARS-CoV-2 antigen (recombinant SARS-CoV-2 spike glycoproteins) has been modified on the surface of AIE 810 NP (AIE 810 NP-SARS-CoV-2 antigen) (Scheme 1a). 34, 35 The hydrodynamic diameter of AIE 810 NP-SARS-CoV-2 antigen (324.3 ± 5.9 nm) is equal to the sum of the hydrodynamic diameter of AIE 810 NP (310.8 ± 4.4 nm) and SARS-CoV-2 antigen (14.5 ± 5.6 nm) (Figure 3a ). The zeta-potential of AIE 810 NP-SARS-CoV-2 antigen (−11.7 ± 1 mV) is between the AIE 810 NP (−21.9 ± 1.1 mV) and SARS-CoV-2 antigen (−7 ± 1 mV) (Figure 3b ). The AIE 810 NP-labeled chicken IgY (AIE 810 NP-chicken IgY) was prepared with a synthetic procedure similar to that used for AIE 810 NP-SARS-CoV-2 antigen. As shown in Figure 3c ,d, the hydrodynamic diameter and zeta-potential of AIE 810 NP-chicken IgY (324.5 ± 2.6 nm and −15.9 ± 0.25 mV) are significantly higher than those of AIE 810 NP. The results indicate that SARS-CoV-2 antigen and chicken IgY are successfully modified on the surface of AIE 810 NP.

Optimization of the preparation conditions is the key parameter to improve the detection performance of the test strip. Here, immunoreaction time before readout and the amount of AIE 810 NP-SARS-CoV-2 antigen were evaluated. As shown in Figure 4a (Figure 4f ). Considering the importance of IgM in early detection, 12.5 μg mL −1 is chosen as the optimal concentration of AIE 810 NP-SARS-CoV-2 antigen. In addition, to achieve the highest signal-to-noise ratio, the concentrations of mouse anti-human IgM (fixed on the M line) and IgG (fixed on the G line) were optimized. The mouse anti-human IgM and IgG were prediluted in phosphate buffer saline to prepare the reserve solution with the final concentrations of 0.3, 0.6, and 1.2 mg mL −1 , respectively, and spotted onto the Pall90 Similarly, there is a good correlation between I G /I C and IgG concentration following an equation of y = −3.818 × e −x/0.557 + 3.563 (R 2 = 0.91) (Figure 5d and Figure S15b , Supporting Information). The limit of detection (LoD) of IgM and IgG is determined to be 0.236 and 0.125 μg mL −1 , respectively, commensurate with that of the ELISA ( Figure S16 , Supporting Information). The low LoD of the AIE 810 NP-based test strip could be attributed to the autofluorescence-free background of the NC membrane/biosample in the NIR region (enhancement of the signal-to-noise ratio) ( Figure S17 , Supporting Information).

A total of 172 serum samples from patients infected with SARS-CoV-2 (1−224 days after symptom onset) were analyzed using AIE 810 NP-based test strips for the detection of IgM and IgG (172 of samples were confirmed as SARS-CoV-2 infection by RT-PCR). Simultaneously, all samples were tested by ELISA and AuNP-based test strips as the control. As shown in Table 1 Monitoring of IgM and IgG in Sequential Clinical Samples. Given its high sensitivity, the AIE 810 NP-based test strip was further extended for monitoring of IgM and IgG in sequential clinical samples. As shown in Table 2 , the IgG or IgM can be observed 8−15 days after symptom onset using AuNP-based test strips, and the IgG or IgM can be observed 1−7 days after symptom onset using ELISA and AIE 810 NPbased test strips. These results demonstrated that the AIE 810 NP-based test strip could earlier detect IgM or IgG in the seroconversion window period than the AuNP-based test strip. Therefore, our developed AIE 810 NP-based test strip could become a promising alternative to AuNP-based test strips and ELISA for the early detection of IgM and IgG in the seroconversion window period.

In summary, we proposed an AIE 810 NP-based lateral flow immunoassay for early detection of IgM and IgG against SARS-CoV-2 in a seroconversion window period. The synthesized AIE 810 NP possesses a large Stokes shift of 145 nm, good photostability, high thermal stability, and strong colloidal stability. Using the NIR emission of AIE 810 NP as the detection signal, the interference of autofluorescence from the NC membrane and human serum was efficiently eliminated, and the sensitivity of the lateral flow test strip was improved. With the homemade portable reader, the LoD of detecting IgM and IgG with an AIE 810 NP-based test strip (0.236 and 0.125 μg mL −1 ) is comparable to that of ELISA (0.040 and 0.039 μg mL −1 ). The sensitivity of AIE 810 NP-based test strips (78 and 95%) in detecting IgM and IgG of 172 COVID samples are comparable to that of ELISA (85 and 95%) and better than that of commercial AuNP-based test strips (41 and 85%). Importantly, AIE 810 NP-based test strips (1−7 days) detect IgM or IgG in sequential clinical samples earlier than commercial AuNP-based test strips (8−15 days). Therefore, the AIE 810 NP-based lateral flow immunoassay can be used as an alternative method for early detection of IgM and IgG against SARS-CoV-2 and displays the great potential for pointof-care clinical diagnosis not only for SARS-CoV-2 but also for other virus outbreaks.

Materials. PS nanoparticles, SARS-CoV-2 specific antigen (recombinant SARS-CoV-2 spike glycoproteins), mouse anti-human IgM, mouse anti-human IgG, a colloidal gold lateral flow immunoassay kit, PVC base, nitrocellulose (NC) membrane (Pall90), absorbent pads, sample pads, and phosphate buffer saline (PBS) were provided by Shanghai Taywell Biotech Co., Ltd. (Shanghai, China). Goat anti-chicken IgY and chicken IgY were purchased from Genstars Biotech CO., Ltd. Bovine serum albumin (BSA), N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide hydrochloride (EDC), and N-hydroxysulfosuccinimide sodium salt (Sulfo-NHS) were purchased from Sigma-Aldrich (Shanghai) Trading Co., Ltd. (Shanghai, China). Human anti-SARS-CoV-2 IgM and IgG were purchased from Novoprotein Scientific Inc. A total of 142 preCOVID samples (including 52 normal serum samples, 44 tuberculosis serum samples, 33 upper respiratory tract infection serum samples, 13 rheumatoid arthritis serum sample), 172 COVID samples, and 26 sequential clinical samples were collected from Anhui Medical University and treated in strict accordance with the standard operation for COVID-19 by the World Health Organization. This study was approved by the institutional review board of Anhui Medical University. All experimental procedures were completed under biosafety level II conditions. Solution preparation details can be found in the Supporting Information.

Characterization. The 1 H NMR and 13 C NMR spectra were collected on a Bruker AV-400 spectrometer. The UV−vis absorption spectrum was recorded on a Shimadzu UV-2600 spectrometer. The NIR emission spectrum was recorded with a modified EK2000-Pro back-thinned fiber spectrometer (Choptics Instruments, Shanghai, China). The dynamic light scattering and zeta-potential results were conducted with a Nano-ZS90 ZetaSizer (Malvern Instruments Ltd., Table 1 . Sensitivity for Detecting IgM and IgG in 172 Serum Samples Using ELISA, AuNP-Based Test Strips, and AIE 810 NP-Based Test Strips ("P" means "Positive", "N" means "Negative" and "S" means "Sensitivity") 30 Briefly, 50 μL of BPBT solution (dissolved by THF, 20 mg mL −1 ) and 250 μL of 40 mg mL −1 PS nanoparticle aqueous solution (containing 0.4 mg sodium dodecyl sulfate) were successively added to 500 μL of acetone aqueous solution. The mixture was stirred at room temperature for 6 h. Afterward, the resultant AIE nanoparticles were separated by centrifugation at 12,000 rpm for 10 min and resuspended in 1 mL of Milli-Q water for further use.

AIE 810 NP Conjugate Preparation. The AIE 810 NP-SARS-CoV-2 antigen conjugation and AIE 810 NP-chicken IgY conjugation were prepared with the EDC-NHS method. 34, 35 Briefly, 50 μL of 10 mg mL −1 EDC solution and 50 μL of 10 mg mL −1 Sulfo-NHS solution (dissolved in borate-buffered saline (BBS), pH 7.4) were successively added to 500 μL of a 4 mg mL −1 AIE 810 NP solution (dissolved by BBS, pH 7.4). The mixture was stirred at room temperature for 30 min. After being activated, the AIE 810 NPs were separated by centrifugation and resuspended in 500 μL of BBS (pH 7.4). Then, 0.25 mg of SARS-CoV-2 antigen was added, and the mixture was stirred for 3 h at room temperature to form a tripartite complex of AIE 810 NP-SARS-CoV-2 antigen. Thereafter, the complex was further blocked by adding 50 μL of 100 mg mL −1 BSA aqueous solution for another 1 h at room temperature. After incubation, the AIE 810 NP-SARS-CoV-2 antigen was centrifuged to remove the unreacted reagent and redispersed in BBS containing 1% BSA and 0.05% proclin300 (pH 7.4) and stored in 4°C for further use. The AIE 810 NP-labeled chicken IgY (AIE 810 NP-chicken IgY) were prepared with a synthetic procedure similar to that used for AIE 810 NP-SARS-CoV-2 antigen.

AIE 810 NP-Based Test Strip Preparation. The test strip was composed of five parts including a plastic adhesive backing pad, a sample pad, a conjugation pad, a NC membrane, and an absorbent pad. Mouse anti-human IgM (0.6 mg mL −1 ), mouse anti-human IgG (0.6 mg mL −1 ), and goat anti-chicken IgY (1.0 mg mL −1 ) prediluted in PBS (pH 6.8, containing 2% sucrose, 1% NaCl) were spotted onto the NC membranes as a test 1 line (M line), test 2 line (G line), and a control line (C line), respectively. The AIE 810 NP-SARS-CoV-2 antigen (5 mg mL −1 ) and AIE 810 NP-chicken IgY (2.5 mg mL −1 ) prediluted in PBS (pH 6.8, containing 2% sucrose, 2% BSA, and 2% NaCl) were spotted onto the conjugation pad followed by drying at 37°C for overnight. Last, the well-assembled test strips were cut to a width of 3.8 mm and fitted into the plastic adhesive backing pad for further use.

AIE 810 NP-Based Test Strip for the Detection of IgM and IgG against SARS-CoV-2 in COVID Samples. The LoD of AIE 810 NPbased test strips was evaluated by detecting a set of calibrators with an IgM and IgG concentration of 0−5 μg mL −1 . A total of 142 preCOVID samples were as negative controls. In preparation, 5 μL of the prepared serum sample was added into 95 μL of running buffer (consisting of BBS, pH 8.0; 0.25% Tween, 0.25% Thesit, and 2% BSA), and the mixture was subsequently added into the sample well. After a 10 min reaction, the fluorescence intensities of the M line (I M ), the G line (I G ), and the C line (I C ) were recorded using a CMOS camera (Huatengwei Vision Technology Co., Ltd., China). The I M /I C and I G /I C were used to calculate the IgM and IgG concentrations in the serum, respectively. For 172 COVID samples and 26 sequential clinical sample detections, 5 μL of the serum sample was added into 95 μL of running buffer, and then the mixture was subsequently added into the sample well. After a 10 min reaction, the fluorescence intensities of the M line (I M ), the G line (I G ), and the C line (I C ) were recorded.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.1c01932. Synthetic route of 4,8-bis(4-(2,2-bis(4(octyloxy)phenyl)-1-phenylvinyl)phenyl)benzo[1,2-c:4,5-c′]bis-[1,2,5]thiadiazole (BPBT); 1 H NMR spectrum of BPBT in CDCl 3 ; 13 C NMR spectrum of BPBT in CDCl 3 ; mass spectrum of BPBT; AIE titration experiment of BPBT; absorption spectra of BPBT in THF and THF/water mixture with different water fractions ( f w ); the hydrodynamic diameter of PS nanoparticles and AIE 810 NP; calculated number of BPBT in an AIE 810 NP; fluorescence spectrum of PS nanoparticles (700 nm long pass filter); QY measurement of AIE 810 NP in aqueous solution; chemical structure of the dye Cy7; UV−vis absorption spectrum (26.3 μM) and emission spectrum (0.35 μM; λ ex = 730 nm) of Cy7 in water; zeta-potential of AIE 810 NP in water (0.2 mg mL −1 ); optimization of the concentration of mouse anti-human IgM and IgG; analytical performance of AIE 810 NP-based test strip; analytical performance of ELISA; autofluorescence of NC membrane/biosample in vis and NIR regions; tables including I G /I C and I M /I C for the detection of IgM and IgG in 142 preCOVID samples using AIE 810 

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The authors thank the National Key R&D Program of China (2017YFA0205100) for financial support. The authors also thank Yong Wu for building the NIR reader.